This invention relates generally to controlled release multiple subunit drug dosage forms, and more particularly to a controlled release drug dosage form which can be adapted for delivery of the drug to the upper gastrointestinal tract concomitantly with the emptying of a meal.
In the treatment of a mammal with a drug it is often desirable to control delivery of the active drug to the intestine of the mammal so as to avoid inactivation of the drug by exposure to gastric pH levels. Moreover, such controlled delivery is useful to avoid irritation of the gastrointestinal mucosa, to control the amount of active drug delivered at a given time, and to increase upper gastrointestinal residence time. It is additionally desirable to maximize contact time of a drug with a meal and the substances secreted in response to the meal. Such control over contact time is especially desirable in exogenous enzyme replacement therapy.
Various techniques and devices are available in the art to control the delivery of an active drug to the duodenum. One such technique utilizes an enteric coating over the dosage form which contains the drug. The enteric coating protects the coated dosage form from dissolution at low gastric pH levels. A further technique involves administration of a dosage from insoluble drug permeable matrices such as waxes, polymers, or ion exchange resins of types which are known in the art. These known dosage forms are plagued with a variety of disadvantages. For example, nondisintegrating forms may cause obstruction in patients with impaired motility. Also, ion exchange resins do not provide complete release of the drug, thereby resulting in wastage of the drug and uncertainty as to the dosage amount.
Certain disease states, such as cystic fibrosis and chronic alcoholism, are characterized by pancreatic insufficiency. Exogenous enzyme replacement is frequently indicated, but there has been a need in the art for a dosage form which will travel concurrent with an ingested meal and release active enzymes in the duodenum in order to approximate the activity of a healthy pancreas. The pancreas normally produces a secretion, which passes through the pancreatic duct into the duodenum and which is essential to the digestion process. The pancreatic secretion contains enzymes such as amylases, lipases, and proteases, the loss of which results in intestinal malabsorption of fats, proteins, and, to a lesser extent carbohydrates. Symptoms of pancreatic insufficiency include abdominal distention, steatorrhea, creatorrhea, rectal prolapse, deficiencies of fat soluble vitamins (A,D,E, and K), hypoproteinemia, anemia, and hypoprothrombinemia.
The primary treatment for pancreatic insufficiency is therefore pancreatic enzyme supplementation, which reduces the amounts of fat and nitrogen excreted unabsorbed. However, the amounts of fat and nitrogen in the stool are only rarely reduced to normal levels at least partially as a result of inactivation of the enzymes by gastric acidity. It is known, however, that other factors are involved since therapy with histamine H.sub.2 -receptor antagonists or antacids, administered concomitant with the enzymes, does not result in a normalization of digestion.
Since pancreatic enzymes are inactivated at gastric pH levels, enteric coatings are commonly utilized to protect the enzymes until they reach the duodenum. Preferably, such a dosage form will release the enzymes in about 5 to 30 minutes since digestion and absorption of metabolites occurs primarily in the upper segment of the intestine, i.e., the duodenum and jejunum. Thus, duodenal pH is a key factor in determining the rapidity with which the formulation releases the enzymes. The more rapidly the enzymes are released, the greater the length of intestine over which the enzymes are available to digest the meal. This leads to better absorption of nutrients from the ingested meal and thereby avoids the undesirable effects listed above which result from large quantities of undigested meal components reaching the colon. However, there is a problem with such enteric coating in that acidic conditions in the duodenum will delay dissolution of the enteric coating, thereby delaying enzyme release until the intestinal contents reach a more distal segment of the intestine with a higher pH. This delay effectively reduces the time during which enzymatic digestion can occur before the meal passes into the colon.
Enteric coatings in commonly used formulations take anywhere from 15 minutes to two hours to dissolve after gastric emptying in normal subjects. Any additional delay resulting from low duodenal pH, as is the case with those suffering from cystic fibrosis, would be expected to compromise the efficacy of the enzymes substantially.
Prior art techniques to deliver drugs such as pancreatin to the duodenum, and thus maximize contact time with the meal and substances secreted in response thereto, include devices of the type disclosed in British Patent No. 1,561,613. This patent describes a dosage unit comprising pancreatin, a distending agent which will exert an osmotic pressure when in aqueous solution, and a basic material contained in a sealed polymeric, semi-permeable film which is resistant to attack by gastric juice. This dosage unit swells in response to the gastric juice. However, the pancreatin is protected from becoming inactivated by operation of the basic material which neutralizes the effects of the gastric juice on the pancreatin. The British patent further teaches that this known dosage form is mechanically ruptured when it is in the region of the pyloric sphincter. It is evident that this known dosage form suffers from an inability to dispense the drug continually, but rather releases the drug all at once when the rupture occurs.
A further known technique is described in British Patent No. 1,509,866 and utilizes a gastric juice soluble capsule having multiple subunits therein which are controlled as to particle size diameter and coated with an enteric coating which dissolves at neutral to alkaline pH levels. The diameters specified in this patent range from about 1.68 to 2.38 mm. Suitable enteric coatings are specified in this patent to include cellulose acetate phthalate plasticized with diethyl phthalate. It is a significant disadvantage of this known dosage form that the high pH-dissolving coating limits the contact time of the pancreatin with the meal. Furthermore, it will be shown hereinbelow that the size and density combinations disclosed in this British patent will result in the drug being emptied at a rate slower than the meal.
It should be noted that exogenous administration of enzymes in large tablets can aggravate the existing physiological condition because large doses of enzymes are released in a small concentrated area resulting in irritation and damage to the intestinal lining and abnormal distribution of enzymes. Moreover, any asynchrony that might exist between the arrival of food and the tablet from the stomach into the duodenum will further reduce the possibility that normal digestion will take place. Non-concomitant arrival of the enzymes with respect to the food results in unpredictable response and poor digestion.
It is evident from the foregoing that significant problems exist in the present state of the art of preparing a suitable drug form for pancreatic enzyme supplementation. For example, there is a need for a proper enteric coating which will ensure delivery of the drug into the duodenum. Additionally, there is a need for a dosage form which releases the enzymes in a biologically active state, and which recreates the conditions of normal pancreatic function. To date, however, pancreatic enzyme supplementation dosages are not available which can be adapted to deliver a drug concomitantly with a meal.
It is to be understood that the treatment of certain disease states by dosage systems which operate concomitantly with a meal represents only one desired, but unachieved, goal in the prior art. Some diseases could be treated effectively by use of dosage systems which deliver an active drug either prior to, or after, emptying of a meal, if such dosage forms were available. Thus, there is a need for a dosage system wherein the time of delivery of an active drug, with respect to the time of ingestion of a meal, can advantageously be selected.
In addition, there is a need for a dosage form for concomitant delivery of a marker with respect to a meal for gastric emptying studies. Currently used markers, such as In-DPTA complexes, measure only the emptying rate of the liquid fraction of the gastric contents, and it is often desired to measure the emptying rate of the solid fraction. Radiolabeled filter paper squares have been used, but are suspected of emptying slower than the meal, and are therefore unreliable as a marker. Gamma-labeled test meals have been used, but extracellularly labeled meals may disadvantageously be subject to gamma label dissociation from the meal into the liquid fraction, thereby rendering this type of marker inaccurate, and intracellularly labeled meals have the disadvantage of being difficult to prepare.
Accordingly, it is an object of the invention to provide a controlled release dosage form having an increased gastric residence time.
It is another object of the invention to provide a controlled release dosage form which can be delivered at the same rate as a meal.
It is further an object of the invention to provide a controlled release dosage form which can be adapted simply, such as by particle size and density combinations, to any desired emptying pattern.
It is also an object of the invention to provide a controlled release dosage form wherein an enteric coating is tailored to the individual pH profile of the gastrointestinal tract of an individual or of a representative sample of individuals in the diseased state.
It is an additional object of the invention to provide a controlled release pancreatic enzyme supplementation system which approximates the conditions of normal digestion.
It is still another object of the invention to provide a marker for studying meal emptying rate which will accurately measure motility functions in the fed state.
It is also another object of the invention to provide a controlled release dosage form which will uniformly dispense throughout the meal.
It is a still further object of the invention to provide a dosage form which will control delivery of the drug to the intestine to increase upper gastrointestinal residence time, avoid irritation of the gastrointestinal mucosa, and/or avoid precipitation of the drug in the bowel.
It is yet an additional object of the invention to provide a dosage form which maximizes contact time of the drug with the meal and with substances secreted in response to the meal.
It is additionally an object of the invention to provide a method of manufacturing a drug which is customized to travel at a predetermined rate with respect to a meal, and to dissolve at a predetermined point within the gastrointestinal tract.